title: Loss of neuronal integrity during progressive HIV-1 infection of humanized mice.
abstract: Neuronal damage induced by ongoing human immunodeficiency virus type 1 (HIV-1) infection was investigated in humanized NOD/scid-IL-2Rγ(c)(null) mice transplanted at birth with human CD34-positive hematopoietic stem cells. Mice infected at 5 months of age and followed for up to 15 weeks maintained significant plasma viral loads and showed reduced numbers of CD4(+) T-cells. Prospective serial proton magnetic resonance spectroscopy tests showed selective reductions in cortical N-acetyl aspartate in infected animals. Diffusion tensor imaging revealed structural changes in cortical gray matter. Postmortem immunofluorescence brain tissue examinations for neuronal and glial markers, captured by multispectral imaging microscopy and quantified by morphometric and fluorescence emission, showed regional reduction of neuronal soma and synaptic architectures. This was evidenced by loss of microtubule-associated protein 2, synaptophysin, and neurofilament antigens. This study is the first, to our knowledge, demonstrating lost neuronal integrity after HIV-1 infection in humanized mice. As such, the model permits studies of the relationships between ongoing viral replication and virus-associated neurodegeneration.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, Radiology, Surgery, and Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Prasanta K
authors.initials: PK
authors.lastname: Dash
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Knibbe
authors.forename: George P
authors.initials: GP
authors.lastname: Casale
authors.forename: Edward
authors.initials: E
authors.lastname: Makarov
authors.forename: Adrian A
authors.initials: AA
authors.lastname: Epstein
authors.forename: Harris A
authors.initials: HA
authors.lastname: Gelbard
authors.forename: Michael D
authors.initials: MD
authors.lastname: Boska
authors.forename: Larisa Y
authors.initials: LY
authors.lastname: Poluektova
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000008:administration & dosage / Q000096:biosynthesis; D003072:Cognition Disorders / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D015658:HIV Infections / Q000276:immunology / Q000473:pathology*; D015497:HIV-1 / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009415:Nerve Net / Q000276:immunology / Q000473:pathology*; D009457:Neuroglia / Q000276:immunology / Q000473:pathology / Q000821:virology; D009474:Neurons / Q000276:immunology / Q000473:pathology* / Q000821:virology; D011446:Prospective Studies; D019562:Viral Load / Q000379:methods; D014779:Virus Replication / Q000276:immunology
chemical_list: D018952:Antigens, CD34